2. Academic Validation
  3. Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog

Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog

  • Commun Biol. 2025 Feb 4;8(1):173. doi: 10.1038/s42003-025-07509-x.
Qin Yan # 1 2,  Yue-Gui Chen # 1,  Xiao-Wen Yang # 2,  An Wang 1,  Xiao-Ping He 2,  Xue Tang 2,  Hong Hu 2,  Kai Guo 2,  Zong-Hua Xiao 2,  Yan Liu 3 4,  Sheng-Hong Li 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
  • 2 Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
  • 3 State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. liuyan@cdutcm.edu.cn.
  • 4 Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. liuyan@cdutcm.edu.cn.
  • 5 State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. shli@mail.kib.ac.cn.
  • 6 Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. shli@mail.kib.ac.cn.
  • # Contributed equally.
PMID: 39905239 DOI: 10.1038/s42003-025-07509-x
Abstract

Cannabinoids are unique meroterpenoids, with cannabigerolic acid (CBGA) serving as a dedicated precursor. This study introduces a Fungal aromatic prenyltransferase AscC into the engineered Escherichia coli to catalyze the transfer of C5-C15 terpenoid linear precursors to olivetolic acid. Four CBGA derivatives (compounds 1-4) with diverse C5, C10, or C15 prenyl chains are isolated and identified, with compound 4 being an undescribed product featuring a C15 prenyl chain at the C-5 position. Compound 4 demonstrates the highest anti-neuroinflammatory and Antibacterial activities, with IC50 values of 3.06 µM for TNF-α and 4.31 µM for IL-6, alongside EC50 values ranging from 0.87 to 3.16 µM against three Gram-positive bacteria. An efficient construct is established by incorporating an additional copy of AscC, resulting in a yield of 14.85 ± 0.91 mg/L of compound 4. Two mutants, L180Y and L180F, are engineered to selectively produce compound 4. These findings provide a foundation for enriching the chemical diversity of bioactive cannabinoid analogs with various prenyl moieties through combinatorial biosynthesis.

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